In this project, we propose to address the functional contribution of hypoxic microenvironment (TME) to the progression of prostate cancer and emergence of metastatic bone disease. This project use the mouse models generated in the Project 1 to study the influence of hypoxia, EMT and myofibroblasts metabolism and validate these finding in human prostate cancer tissue. Such studies will be performed in collaboration Scadden Laboratory (Project 3), which will determine the cellular components of the bone that likely cooperate with bone metastasis. We also propose to evaluate in detail the acquisifion of the ability of cancer cell to mimic mesenchymal cell types and undergo a program of epithelial to mesenchymal transition (EMT), in hopes of gathering information to identify new therapeutic targets against metastatic prostate cancer.